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Abstract
The pathogenesis of atherosclerosis involves dysfunctions of vascular endothelial cells and smooth muscle cells as well as blood borne inflammatory cells such as monocyte-derived macrophages. In vitro experiments towards a better understanding of these dysfunctions are typically performed in two-dimensional cell culture systems. However, these models lack both the three-dimensional structure and the physiological pulsatile flow conditions of native arteries. We here describe the development and initial characterization of a tissue engineered artery equivalent, which is composed of human primary endothelial and smooth muscle cells and is exposed to flow in vitro. Histological analyses showed formation of a dense tissue composed of a tight monolayer of endothelial cells supported by a basement membrane and multiple smooth muscle cell layers. Both low (LDL) and high density lipoproteins (HDL) perfused through the artery equivalent were recovered both within endothelial cells and in the sub-endothelial intima. After activation of the endothelium with either tumour necrosis factor alpha (TNFα) or LDL, monocytes circulated through the model were found to adhere to the activated endothelium and to transmigrate into the intima. In conclusion, the described tissue engineered human artery equivalent model represents a significant step towards a relevant in vitro platform for the systematic assessment of pathogenic processes in atherosclerosis independently of any systemic factors.
Highlights
Atherosclerosis is responsible for a substantial global disease load and remains a major cause of morbidity and mortality worldwide
One of the first events in the pathogenesis of atherosclerosis is the insudation of cholesterol-rich low density lipoprotein (LDL) into the innermost intimal layer of the arterial wall where they are bound by proteoglycans and eventually modified [1]
Immunohistochemistry staining showed the presence of a-smooth muscle actin positive cells in the inner layer of the vessel and CD31 positive cells forming a monolayer on the luminal side (Fig. 2 D-E)
Summary
Atherosclerosis is responsible for a substantial global disease load and remains a major cause of morbidity and mortality worldwide. Within the arterial intima the monocytes differentiate into macrophages which upon receptor mediated uptake of LDL are transformed into foam cells They form the early ‘‘fatty streak’’ lesion [2]. The classical potentially antiatherogenic property is related to its ability to remove cholesterol from the macrophage foam cells within the arterial wall and mediate the transport to the liver for excretion into the bile [3]. To do this HDL must cross the endothelial barrier in order to get access to the cholesterol-loaded macrophages [3]
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